Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice.

Bo Xia,Guo He Cai,Grant A. Mitchell,Jiang Wei Wu,Hao Yang,Shu Pei Wang,Gregory S. Barsh

doi:10.1371/journal.pgen.1007110

Abstract

Fatty liver is a major health problem worldwide. People with hereditary deficiency of hormone-sensitive lipase (HSL) are reported to develop fatty liver. In this study, systemic and tissue-specific HSL-deficient mice were used as models to explore the underlying mechanism of this association. We found that systemic HSL deficient mice developed fatty liver in an age-dependent fashion between 3 and 8 months of age. To further explore the mechanism of fatty liver in HSL deficiency, liver-specific HSL knockout mice were created. Surprisingly, liver HSL deficiency did not influence liver fat content, suggesting that fatty liver in HSL deficiency is not liver autonomous. Given the importance of adipose tissue in systemic triglyceride metabolism, we created adipose-specific HSL knockout mice and found that adipose HSL deficiency, to a similar extent as systemic HSL deficiency, causes age-dependent fatty liver in mice. Mechanistic study revealed that deficiency of HSL in adipose tissue caused inflammatory macrophage infiltrates, progressive lipodystrophy, abnormal adipokine secretion and systemic insulin resistance. These changes in adipose tissue were associated with a constellation of changes in liver: low levels of fatty acid oxidation, of very low density lipoprotein secretion and of triglyceride hydrolase activity, each favoring the development of hepatic steatosis. In conclusion, HSL-deficient mice revealed a complex interorgan interaction between adipose tissue and liver: the role of HSL in the liver is minimal but adipose tissue deficiency of HSL can cause age-dependent hepatic steatosis. Adipose tissue is a potential target for treating the hepatic steatosis of HSL deficiency.

Highlights

IntroductionDisorders of lipid accumulation such as obesity and fatty liver (hepatic steatosis) are among the greatest risk factors for health in developed countries [1,2,3,4]
Disorders of lipid accumulation such as obesity and fatty liver are among the greatest risk factors for health in developed countries [1,2,3,4]
Fatty liver is a major complication of obesity and of type 2 diabetes mellitus

Summary

Introduction

Disorders of lipid accumulation such as obesity and fatty liver (hepatic steatosis) are among the greatest risk factors for health in developed countries [1,2,3,4]. Hepatic steatosis is linked to the development of liver fibrosis, cirrhosis and cancer [5, 6] and is rapidly increasing in prevalence [7, 8]. Increasing interest centers on the biology of triglyceride (TG)-containing cytoplasmic lipid droplets, TG synthesis and TG degradation (lipolysis). After the initial cleavage of a TG to a diacylglycerol (DG) plus a fatty acid (FA), performed by adipose triglyceride lipase (ATGL) [9], HSL-mediated hydrolysis of DG to a monoacylglycerol (MG) plus a FA [10]. Systemic ATGL deficiency causes hepatic steatosis [11, 12]. By using liver-specific ATGL deficient mouse models, we and others further showed that ATGL deficiency in liver causes marked hepatic steatosis in mice, suggesting that the underlying mechanism of ATGL-related hepatic steatosis is liver autonomous [13, 14]

Methods

Results

Discussion

Conclusion